US7553839B2 - 5h-pyrrolo[3,2-D] pyrimidine inhibitors of nucleoside phosphorylases and nucleosidases - Google Patents

5h-pyrrolo[3,2-D] pyrimidine inhibitors of nucleoside phosphorylases and nucleosidases Download PDF

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US7553839B2
US7553839B2 US10/524,995 US52499505A US7553839B2 US 7553839 B2 US7553839 B2 US 7553839B2 US 52499505 A US52499505 A US 52499505A US 7553839 B2 US7553839 B2 US 7553839B2
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acid
hydroxy
pyrrolidine
methyl
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Gary Brian Evans
Richard Hubert Furneaux
Dirk Henning Lenz
Vern L. Schramm
Peter Charles Tyler
Olga Vladimirovna Zubkova
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Albert Einstein College of Medicine
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
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    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Definitions

  • This invention relates to certain nucleoside analogues which are inhibitors of PNP, PPRT, MTAP, MTAN, and/or NH, the use of these compounds as pharmaceuticals and pharmaceutical compositions containing the compounds.
  • the invention also relates to methods of treating diseases.
  • U.S. Pat. Nos. 5,985,848, 6,066,722 and 6,228,741 are directed to nucleoside analogues that are inhibitors of purine nucleoside phosphorylase (PNP) and purine phosphoribosyltransferases (PPRT).
  • PNP purine nucleoside phosphorylase
  • PPRT purine phosphoribosyltransferases
  • the analogues are useful in treating parasitic infections, T-cell malignancies, autoimmune diseases and Inflammatory disorders.
  • the analogues are also useful for immunosupression in organ transplantation.
  • PCT/NZ00/00048 provides a process for preparing certain PNP inhibitor compounds. This application recognises the compounds as PNP inhibitors and addresses a need for simpler methods of preparing them. PCT/NZ01/00174 also provides further nucleoside analogues that are inhibitors of PNP and PPRT.
  • nucleoside analogues have also been identified as potent inhibitors of 5′-methylthioadenosine phosphorylase (MTAP) and 5′-methylthioadenosine nucleosidase (MTAN). These are the subject of PCT/NZ03/00050.
  • MTAP 5′-methylthioadenosine phosphorylase
  • MTAN 5′-methylthioadenosine nucleosidase
  • PNP catalyses the phosphorolytic cleavage of ribo- and deoxyribonucleosides, for example those of guanine and hypoxanthine, to give the corresponding sugar-1-phosphate and guanine, hypoxanthine or other purine bases.
  • PNP purine nucleoside phosphorylase
  • Nucleoside hydrolases catalyse the hydrolysis of nucleosides. These enzymes are not found in mammals but are required for nucleoside salvage in some protozoan parasites. Some protozoan parasites use nucleoside phosphorylases either instead of or in addition to nucleoside hydrolases for this purpose. Inhibitors of nucleoside hydrolases and phosphorylases can be expected to interfere with the metabolism of the parasite and can therefore be usefully employed against protozoan parasites.
  • MTAP and MTAN function in the polyamine biosynthesis pathway, in purine salvage In mammals, and in the quorum sensing pathways in bacteria.
  • MTAP catalyses the reversible phosphorolysis of 5′-methylthioadenosine (MTA) to adenine and 5-methylthio- ⁇ -D-ribose-1-phosphate (MTR-1P).
  • MTAN catalyses the reversible hydrolysis of MTA to adenine and 5-methylthio- ⁇ -D-ribose and of S-adenosyl-L-homocysteine (SAH) to adenine and S-ribosyl-homocysteine (SRH).
  • SAH S-adenosyl-L-homocysteine
  • the adenine formed is subsequently recycled and converted into nucleotides. Essentially, the only source of free adenine in the human cell is a result of the action of these enzymes.
  • the MTR-1P is subsequently converted into methionine by successive enzymatic actions.
  • MTA is a by-product of the reaction involving the transfer of an aminopropyl group from decarboxylated S-adenosylmethionine to putrescine during the formation of spermidine.
  • the reaction is catalyzed by spermidine synthase.
  • the spermidine synthase is very sensitive to product inhibition by accumulation of MTA. Therefore, inhibition of MTAP or MTAN severely limits the polyamine biosynthesis and the salvage pathway for adenine in the cells.
  • MTA is the by-product of the bacterial synthesis of acylated homoserine lactones from S-adenosylmethionine (SAM) and acyl-acyl carrier proteins in which the subsequent lactonization causes release of MTA and the acylated homoserine lactone.
  • SAM S-adenosylmethionine
  • acyl-acyl carrier proteins in which the subsequent lactonization causes release of MTA and the acylated homoserine lactone.
  • the acylated homoserine lactone is a bacterial quorum sensing molecule in bacteria that is involved in bacterial virulence against human tissues. Recent work has identified a second communication system (autoinducer 2, Al-2) that is common to both Gram-positive and Gram-negative bacteria and thus has been proposed as a “universal signal” which functions in interspecies cell-to-cell communication.
  • MTAN generates S-ribosyl-homocysteine (SRH) that is the precursor of Al-2.
  • S-ribosyl-homocysteine S-ribosyl-homocysteine
  • Inhibition of MTAN or MTAP in microbes will prevent MTA removal and subject the pathway to product inhibition, thereby decreasing production of the quorum sensing pathway and decreasing the virulence of microbial infections.
  • Inhibition of MTAN in microbes will prevent the formation of SRH, decreasing the production of the second quorum sensing pathway.
  • MTAP deficiency due to a genetic deletion has been reported with many malignancies.
  • the loss of MTAP enzyme function in these cells is known to be due to homozygous deletions on chromosome 9 of the closely linked MTAP and p16/MTS1 tumour suppressor gene.
  • p16/MTS1 is probably responsible for the tumour, the lack of MTAP activity is a consequence of the genetic deletion and is not causative for the cancer.
  • the absence of MTAP alters the purine metabolism in these cells so that they are mainly dependent on the de novo pathway for their supply of purines. That makes these cells unusually sensitive to inhibitors like methotrexate, alanosine and azaserine, that block the de novo pathway. Therefore, a combination therapy of methotrexate, alanosine or azaserine with an MTAP inhibitor will have unusually effective anti-tumour properties.
  • MTAP inhibitors would also be very effective against parasitic infection such as malaria that infects red blood cells (RBCs), as they lack the de novo pathway for purine biosynthesis.
  • RBCs red blood cells
  • Protozoan parasites depend entirely upon the purines produced by the salvage pathway for their growth and propagation. MTAP inhibitors will therefore kill these parasites without having any negative effect on the host RBCs, as RBCs are terminally differentiated cells and they do not synthesize purines, produce polyamines or multiply.
  • the imino sugar part of the compounds described most of the patent specifications referred to above has the nitrogen atom located between C-1 and C-4 so as to form 1,4-dideoxy-1,4-imino-D-ribitol compounds.
  • the location of the nitrogen atom in the ribitol ring may be critical for binding to enzymes.
  • the location of the link between the sugar part and the nucleoside base analogue may be critical for enzyme inhibitory activity.
  • the known compounds have that link at C-1 of the sugar ring.
  • nucleoside phosphorylase and nucleosidase inhibitors In the search for new and improved nucleoside phosphorylase and nucleosidase inhibitors, the applicants have investigated the synthesis and bioactivity of compounds where the location of the nitrogen atom in the sugar ring is varied and, additionally; where two nitrogen atoms form part of the sugar ring. Alternative modes of linking the sugar part and the base analogue have also been investigated.
  • Z is selected from hydrogen, halogen, hydroxy, SQ and OQ. More preferably Z is OH. Alternatively it is preferred that Z is SQ. In another preferred embodiment, Z is Q.
  • V is CH 2 . It is further preferred that X is CH 2 . Additionally, it is preferred that G is CH 2 .
  • W is NR 1 .
  • W is NR 2 .
  • W is also preferred that where W is selected from NH, NR 1 or NR 2 then X is CH 2 .
  • Preferred compounds of the invention include those where V, X and G are all CH 2 , Z is OH and W is NR 1 .
  • V, X and G are all CH 2 , Z is SQ and W is NR 1 .
  • Y is hydrogen.
  • Y is hydroxy.
  • B is hydroxy.
  • B is NH 2 .
  • A is CH. Alternatively it is preferred that A is N.
  • D is H.
  • D is NH 2 .
  • E is N.
  • Preferred compounds of the invention include:
  • the invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) as defined above.
  • the invention provides a method of treating a disease or condition in which it is desirable to inhibit purine phosphoribosyltransferase, purine nucleoside phosphorylase, 5′-methylthioadenosine phosphorylase, 5′-methylthioadenosine nucleosidase and/or nucleoside hydrolase comprising administering a pharmaceutically effective amount of a compound of formula (I) as defined above to a patient requiring treatment.
  • the disease or condition may include cancer, bacterial infection, protozoal infection or a T-cell mediated disease.
  • the T-cell mediated disease may be psoriasis, arthritis or transplant rejection.
  • the invention provides the use of a compound of formula (I) as defined above in the manufacture of a medicament for treating a disease or condition in which it is desirable to inhibit purine phosphoribosyltransferase, purine nucleoside phosphorylase, 5′-methylthioadenosine phosphorylase, 5′-methylthioadenosine nucleosidase and/or nucleoside hydrolase.
  • the compounds of the invention may be prepared by any suitable method.
  • One suitable method involves independently synthesising the sugar part and the base part and then linking the base part to a nitrogen atom in the ring of the sugar part.
  • Scheme 1 outlines the preparation of the 1-N-imino sugar part of a compound of the invention where the nitrogen atom of the sugar analogue is located at the same position as the C-1 anomeric carbon atom would be found in a sugar molecule.
  • a useful starting compound in the synthesis of the 1-N-iminosugar is N-tert-butoxycarbonyl-(3R,4S)-3-hydroxy-4-[(1S)-1,2-dihydroxyethyl]pyrrolidine. This starting compound may be prepared via the method of Filichev et al.
  • Benzylation of the hydroxyl groups of compound (1) before removal of the N protecting group may be desirable to give (3R,4R)-3-benzyloxy-4-benzyloxymethylpyrrolidine hydrochloride (3) as a useful compound ready for linking to a suitable base analogue.
  • the linking of the sugar part may be achieved by reductive amination of an appropriate aldehyde.
  • suitable aldehydes prepared from their corresponding bromo precursors, are shown in Scheme 2.
  • any sugar analogue having a nitrogen atom at any location in its ring may be coupled to any base analogue in this way. It is also to be appreciated that methods other than coupling by reductive amination of an aldehyde may be used.
  • 3R,4S)-4-Hydroxy-3-hydroxymethylpyrazolidine (21) may be prepared according to the route outlined in Scheme 6.
  • the ketone (14) is prepared from D-xylose using well known chemistry (Lin, T-S., Zhu, J-L., Dutschman, G. E., Cheng, Y-C., Prusoff, W. H., J. Med. Chem. 1993, 36, 353-362).
  • Amination followed by reduction of the imine and acetylation of the resulting secondary amine gives compound (17).
  • the key step of acid hydrolysis with concomitant recyclisation gives the imino cycle (18).
  • Hydrogenation followed by cleavage of the diol moiety and removal of the acetate provides the desired pyrazolidine (21).
  • the pyrazolidine (21), or the precursor N-acetate (20), may be coupled with a variety of base analogues to give potential inhibitors of the formula (I) of this invention.
  • hydrochloride salt (25) which can be used in a Mannich-type reaction to provide (3R,4R)-1-[(6-chloro-9-deazapurin-9-yl)methyl]-3-hydroxy-4-(2-phenylethyl)pyrrolidine (26).
  • Treatment with 7 N ammonia in methanol at 130° C. in a sealed tube followed by the transformation to the hydrochloride salt with 3N aqueous HCl gives (3R,4S)-1-[(9-deazaadenin-9-yl)methyl]-3-hydroxy-4-(2-phenylethyl)pyrrolidine hydrochloride (27).
  • Scheme 8 shows still another alternative for the preparation of selected compounds of the invention. This procedure uses the starting compound D-arabinitol, rather than N-tert-butoxycarbonyl-(3R,4S)-3-hydroxy-4-[(1S)-1,2-dihydroxyethyl]pyrrolidine.
  • the compounds of the invention are potent Inhibitors of PNP, MTAP and/or MTAN.
  • Table 1 shows inhibition constants for selected compounds of the invention against human PNP.
  • Table 2 shows Inhibition constants for selected compounds against E. coli MTAN.
  • Table 3 shows inhibition constants for selected compounds against human MTAP.
  • Table 4 shows inhibition constants for selected compounds against Mycobacterium tuberculosis PNP.
  • Table 5 shows inhibition constants for selected compounds against Plasmodium falciparum PNP.
  • K i as shown in Tables 1, 2, 3 4 and 5 is the initial inhibition constant formed by the enzyme-inhibitor complex, and K i * is the equilibrium dissociation constant for inhibition that is observed following a period of slow-onset, tight binding inhibition. Ki* is the biologically effective constant.
  • the compounds of the invention are useful in both free base form and in the form of salts.
  • pharmaceutically acceptable salts is intended to apply to non-toxic salts derived from inorganic or organic acids, including, for example, the following acids: hydrochloric, sulphuric, phosphoric, acetic, lactic, fumaric, succinic, tartaric, gluconic, citric, methanesulfonic and p-toluenesulfonic acids.
  • the active compounds may be administered to a patient by a variety of routes, including oral administration, injection, or topical administration.
  • the amount of compound to be administered will vary widely according to the nature of the patient and the nature and extent of the disorder to be treated. Typically the dosage for an adult human will be in the range less than 1 to 1000 milligrams, preferably 0.1 to 100 milligrams.
  • the compounds can be formulated into solid or liquid preparations, for example tablets, capsules, powders, solutions, suspensions and dispersions. Such preparations are well known in the art as are other oral dosage regimes not listed here.
  • the compounds may be tableted with conventional tablet bases such as lactose, sucrose and corn starch, together with a binder, a disintegration agent and a lubricant.
  • the binder may be, for example, corn starch or gelatin
  • the disintegrating agent may be potato starch or alginic acid
  • the lubricant may be magnesium stearate.
  • Other components such as colourings or flavourings may be added.
  • Liquid forms include carriers such as water and ethanol, with or without other agents such as a pharmaceutically acceptable surfactant or suspending agent.
  • the compounds may also be administered by injection in a physiologically acceptable diluent such as water or saline.
  • a physiologically acceptable diluent such as water or saline.
  • the diluent may comprise one or more other ingredients such as ethanol, propylene glycol, an oil or a pharmaceutically acceptable surfactant.
  • the compounds may be present as ingredients in creams, for topical administration to skin or mucous membranes.
  • the creams include a pharmaceutically acceptable solvent to assist passage through the skin or mucous membranes.
  • Suitable creams are well known to those skilled in the art.
  • the compounds may further be administered by means of sustained release systems.
  • they may be incorporated into a slowly dissolving tablet or capsule.
  • FIG. 1 shows the kinetic curves for human PNP inhibited by compound (8).
  • FIG. 2 shows in vivo inhibition of mouse MTAP.
  • N-tert-Butoxycarbonyl-(3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidine (1). N-tert-Butoxycarbonyl-(3R,4S)-3-hydroxy-4-[(1S)-1,2-dihydroxyethyl]pyrrolidine (3.4 g, 13.7 mmol) in ethanol (50 mL) was added dropwise to a stirred solution of sodium periodate (3.4 g, 16 mmol) in water (25 mL) while maintaining the reaction temperature at 0° C. The reaction was left an additional 20 min after which time sodium borohydride (2.0 g, excess) was added portionwise while again ensuring the reaction temperature was maintained at 0° C. On complete addition the solid was filtered, washed with ethanol (50 mL) and concentrated in vacuo to afford a syrup. Chromatography afforded 1 (2.74 g, 92%) as a syrup.
  • N-tert-Butoxycarbonyl-(3R,4S)-3-hydroxy-4-(2-phenylethyl)pyrrolidine (24)
  • ethanol 20 mL
  • Pd/C 10% Pd/C
  • the suspension was stirred under an atmosphere of hydrogen for 12 h.
  • the solvent was removed in vacuo to give 254 mg (87%) of the title compound as a syrup.
  • N-(9-Deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol hydrochloride (40.HCl).
  • the N-cyanomethyl derivative 39 (0.5 g, 1.53 mmol) was converted into the title compound by the same sequence of reactions described previously in the preparation of Immucillin-H (Evans, G. B.; Furneaux, R. H.; Gainsford, G. J.; Schramm, V. L.; Tyler, P. C. Tetrahedron 2000, 56, 3053-3062) to give 40.HCl as an amorphous powder (0.07 g, 0.23 mmol, 15%).
  • N-(9-Deazahypoxanthin-9-yl)methyl-1,4-dideoxy-1,4-imino-D-ribitol hydrochloride (41.HCl).
  • the aldehyde (5a) (114 mg, 0.38 mmol) was added to a solution of 38 (Horenstein, B. A.; Zabinski, R. F.; Schramm, V. L. Tetrahedron Lett. 1993, 34, 7213-7216) (100 mg, 0.35 mmol) in methanol (1.5 mL), THF (0.5 mL) and acetic acid (100 ⁇ L) and the mixture was stirred for 10 min.
  • (3R,4R)-1-[(9-Deazaguanin-9-yl)methyl]-3-hydroxy-4-hydroxymethylpyrrolidine (61).
  • (3R,4R)-3-Hydroxy-4 (hydroxymethyl)pyrrolidine hydrochloride (4) (154 mg, 1.0 mmol) and sodium acetate (82 mg, 1.0 mmol) were dissolved in water (2 mL) and to the solution were added aqueous formaldehyde (82 ⁇ L, 1.0 mmol) and deazaguanine (120 mg, 0.8 mmol). The reaction was stirred at 95° C. for 12 h. Silica gel (1.0 g) was added and the mixture was evaporated to dryness.
  • the reaction involves the conversion of inosine (1 mM) and inorganic phosphate (50 mM, pH 7.4) to hypoxanthine and ⁇ -D-ribose 1-phosphate. Analysis by this method requires that the inhibitor concentration be present at least 10 ⁇ the enzyme concentration. Enzyme was present at 1.6 ⁇ M. The reaction progress was followed in a coupled assay by monitoring the formation of uric acid from oxidation of hypoxanthine by xanthine oxidase (128 ⁇ g; 59 munits/ml reaction mixture). The inhibitor concentration from 0 to 1 nM was used to determine the initial dissociation constant.
  • K i was determined from the time interval of 0 to 4 min and the equilibrium dissociation constant K i * was determined from the time interval from 35 to 45 min.
  • the kinetic curves for human PNP inhibited by compound (8) are shown in FIG. 1 ; the concentration of inhibitor is indicated on the right hand side.
  • Continuous spectrophotometric assays as well as discontinuous assays were used to characterize the inhibitors of the invention and in vivo inhibition of MTAP and/or MTAN.
  • the conversion of MTA into adenine was measured as a decrease in absorbance at 274 nm.
  • the difference in spectral properties is maximum and the millimolar extinction coefficient (cm ⁇ 1 ) is 1.6 for the conversion of MTA to adenine.
  • MTAP activity in blood samples 6 ⁇ L of a mixture containing 1:1 blood:0.6% Triton X-100 was added to the assay mixture described above and samples taken at appropriate times for analysis by thin layer chromatography. Assays for MTAP activity from mouse liver were accomplished in a similar manner. Liver extracts (3 ⁇ L) containing approximately 100 ⁇ g of protein were added to the assay mixtures for appropriate times followed by analysis by thin layer chromatography.
  • the kinetics for slow onset inhibition and the measurement of K i and K i * values were carried out by adding enzyme of known concentration (1 to 5 nM) to reaction mixtures having high concentrations of substrate and various concentrations of inhibitors.
  • Substrate concentrations of 150 ⁇ M were typically used for MTA nucleosidase and 200 ⁇ M for MTA phosphorylase. These concentrations correspond to an OD between 0.7 and 1.1 at 274 nM.
  • the formation of product is monitored as a decrease in absorbance at 274 nm.
  • Conditions for K i * determination used high concentration of substrate. Two controls, one having no inhibitor and other no enzyme were included in the experiment.
  • the K i values of these enzymes for the inhibitors were calculated by fitting in the ratio of initial rates in the presence of inhibitor to those without inhibitor versus the inhibitor concentration, for the known K m and substrate concentration into the following expression:
  • V o ′ V o K m + [ S ] K m + [ S ] + K m ⁇ [ I ] K i
  • V s ′ V s K m + [ S ] K m + [ S ] + K m ⁇ [ I ] K i *
  • V s ′ is the steady-state rate following attainment of equilibrium in the presence inhibitor
  • V s is the steady-state rate in the control having no inhibitor.
  • a mouse was fed 200 micrograms of Compound 57, and samples of blood were taken as a function of time. Cells were lysed and assayed for residual MTAP activity in assay mixtures containing MTA. The assay measures the release of adenine from [2,8- 3 H]MTA. The results are shown in FIG. 2 .
  • the present invention relates to compounds that are inhibitors of PNP, PPRT, MTAP, MTAN and/or NH.
  • the compounds are therefore expected to be useful in the treatment of diseases in which the inhibition of PNP, PPRT, MTAP, MTAN and/or NH is desirable.
  • diseases include cancer, bacterial infection, protozoal infection or T-cell mediated diseases.

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